We propose an integrated program of basic and translational research to develop foamy virus (FV) vector- based gene replacement therapy for patients who suffer from the inherited severe combined immunodeficiency SCID-X1. The program involves three scientific Projects and four Cores. Two of the scientific projects are focused on studying FV vector SCID-X1 gene therapy using animal models: Project 1 - Pre-clinical modeling of FV gene therapy for murine and human SCID-X1, and Project 2 - FV mediated gene therapy in the canine SCID-X1 model. These projects will test key hypotheses regarding the safety and efficacy of FV vectors applied in conjunction with advanced non-myeloablative conditioning regimens for ?c gene replacement therapy. The other scientific project, Project 3 - Second generation approaches to FV vector SCID-X1 gene therapy, will test key hypotheses related to FV vector systems and technology, with the goal of further enhancing FV vector safety and performance. The three Projects will be supported by four Cores to provide for efficient use of common methods and technology. Over the five year period of support, the program is designed to yield an integrated gene replacement therapy for SC1D-X1 consisting of a well characterized 1st generation clinical ?c FV vector and an advanced conditioning regimen that is fully ready for translation to a human SCID-X1 clinical trial. In addition, the program wil advance our knowledge of FV vector systems and FV vector technology; and initiate pre-clinical evaluation of 2nd generation ?c FV vector systems and integrated therapies anticipated to lead to future further advances in safety and efficacy. Overall, our work is predicted to lead to safe and novel future therapies, including efficient methods for direct in vivo FV vector gene delivery, needed for human SCID-X1 as well other genetic disorders.